U.S. Pat. No. 4,105,776 to Ondetti et al discloses proline derivatives which are angiotensin converting enzyme (ACE) inhibitors and have the general formula ##STR1## wherein R is hydroxy, NH.sub.2 or lower alkoxy;
R.sub.1 and R.sub.4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl; PA1 R.sub.2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoyl-amidomethyl, ##STR2## R.sub.6 --S--, or R.sub.7 ; R.sub.3 is hydrogen, hydroxy or lower alkyl; PA1 R.sub.5 is lower alkyl, phenyl or phenyl-lower alkyl; PA1 R.sub.6 is lower alkyl, phenyl, substituted phenyl (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkyl or amino(carboxy)lower alkyl; ##STR3## M is O or S; m is 1 to 3; PA1 n and p each is 0 to 2. PA1 R.sub.3 is hydrogen or lower alkyl; PA1 R.sub.4 is hydrogen, lower alkyl, phenyl-lower alkyl or a metal ion; and PA1 n is 0 or 1. PA1 one of R.sub.2 and R.sub.4 is ##STR6## and the other is hydrogen, alkyl, arylalkyl or ##STR7## wherein X is hydrogen, alkyl or phenyl and Y is hydrogen, alkyl, phenyl or alkoxy, or together X and Y are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH-- or ##STR8## R.sub.3 is hydrogen or alkyl; --R.sub.5 --COOR.sub.4 is ##STR9## R.sub.6 is hydrogen, hydroxy, alkyl, halogen, azido, amino, cycloalkyl, aryl, arylalkyl, carbamoyloxy, N,N-dialkylcarbamoyloxy, or --Z--R.sub.9 ; PA1 R.sub.7 and R'.sub.7 are the same and each is halogen or --Z--R.sub.10, or R.sub.7 and R'.sub.7 together are .dbd.O, --O--(CH.sub.2).sub.m --O-- or --S--(CH.sub.2).sub.m --S--; PA1 R.sub.8 is hydrogen and R'.sub.8 is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl or R.sub.8 and R'.sub.8 together are .dbd.O; PA1 R.sub.9 is alkyl, aryl, arylalkyl, 1- or 2-naphthyl, or biphenyl; PA1 R.sub.10 is alkyl, aryl or arylalkyl; PA1 Z is oxygen or sulfur; PA1 n is 0 or 1; and PA1 m is 1 or 2. PA1 R.sub.14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy. PA1 m is zero, one, two or three. PA1 p is one, two or three provided that p is more than one only if R.sub.13 or R.sub.14 is hydrogen, methyl, methoxy, chloro, or fluoro. PA1 R.sub.15 is hydrogen or lower alkyl of 1 to 4 carbons. PA1 Y is oxygen or sulfur. PA1 R.sub.16 is lower alkyl of 1 to 4 carbons, ##STR26## or the R.sub.16 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent. PA1 R.sub.4 is hydrogen, lower alkyl, cycloalkyl, or ##STR27## R.sub.5 is hydrogen, lower alkyl, ##STR28## --(CH.sub.2).sub.r --NH.sub.2, --(CH.sub.2).sub.r --SH, --(CH.sub.2).sub.r --S--lower alkyl, ##STR29## r is an integer from 1 to 4. R.sub.1 is hydrogen, lower alkyl, or cycloalkyl. PA1 R.sub.2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR30## --(CH.sub.2).sub.r --NH.sub.2, --(CH.sub.2).sub.r --SH, --(CH.sub.2).sub.r --S--lower alkyl, ##STR31## or R.sub.1 and R.sub.2 taken together are --(CH.sub.2).sub.n -- wherein n is an integer from 2 to 4. PA1 R.sub.3 and R.sub.6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, or ##STR32## wherein R.sub.17 is hydrogen, lower alkyl, or phenyl, and R.sub.18 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R.sub.17 and R.sub.18 taken together are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3, --CH.dbd.CH, or ##STR33## R.sub.19 is lower alkyl, benzyl, or phenethyl. R.sub.20 is hydrogen, lower alkyl, benzyl or phenethyl. PA1 R.sub.21 is alkyl of 1 to 10 carbons, ##STR34## wherein q is zero or an integer from 1 to 7 and R.sub.14, p and m are as defined above. PA1 R.sub.22 and R.sub.23 are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, ##STR35## wherein m, R.sub.14, and p are as defined above. PA1 R.sup.1 is hydrogen, alkyl of from 1 to 20 carbon atoms which include branched and cyclic and unsaturated (such as allyl) alkyl groups, substituted loweralkyl wherein the substituent can be halo, hydroxy, lower alkoxy, aryloxy such as phenoxy, amino, diloweralkylamino, acylamino, such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio such as phenylthio, carboxy or carboxamido, carboloweralkoxy, aryl such as phenyl or naphthyl, substituted aryl such as phenyl wherein the substituent is lower alkyl, lower alkoxy or halo, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl such as benzyl, styryl or indolyl ethyl, substituted arloweralkyl, substituted arloweralkenyl, substituted heteroarlower alkyl, or substituted heteroarlower alkenyl, wherein the substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, acylamino (acetylamino or benzoylamino) diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl, cyano or sulfonamido; arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino (acetylamino or benzoylamino); PA1 R.sup.2 and R.sup.7 are the same or different and are hydrogen or lower alkyl; PA1 R.sup.3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (such as benzoylamino lower alkyl, acetylamino lower alkyl), amino lower alkyl, dimethylamino lower alkyl, halo lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkyl thio lower alkyl; PA1 R.sup.4 is hydrogen or lower alkyl; PA1 R.sup.5 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkylthio lower alkyl; PA1 R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above substituted with hydroxy, loweralkoxy, lower alkyl or dilower alkyl; PA1 and the pharmaceutically acceptable salts thereof.
The asterisks indicate asymmetric carbon atoms. Each of the carbons bearing a substituent R.sub.1, R.sub.3 and R.sub.4 is asymmetric when that substituent is other than hydrogen.
U.S. Pat. No. 4,168,267 to Petrillo discloses phosphinylalkanoyl prolines which have the formula ##STR4## wherein R.sub.1 is lower alkyl, phenyl or phenyl-lower alkyl; R.sub.2 is hydrogen, phenyl-lower alkyl or a metal ion;
U.S. application Ser. No. 212,911 to Petrillo filed Dec. 4, 1980 discloses phosphinylalkanoyl substituted prolines having the formula ##STR5## or a salt thereof, wherein R.sub.1 is alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
U.S. application Ser. No. 289,671 to Karanewsky et al, filed Aug. 3, 1981, discloses phosphonamidate substituted amino or imino acids which are angiotensin converting enzyme inhibitors and salts thereof and have the formula ##STR10## wherein X is an imino or amino acid of the formula ##STR11## R.sub.7 is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR12## azido, amino, ##STR13## a 1- or 2-naphthyl of the formula ##STR14## --(CH.sub.2).sub.m --cycloalkyl, ##STR15## --O--lower alkyl, ##STR16## a 1- or 2-naphthyloxy of the formula ##STR17## --S--lower alkyl, ##STR18## or a 1- or 2-naphthylthio of the formula ##STR19## R.sub.8 is keto, halogen, ##STR20## --O--lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR21## --S--lower alkyl, ##STR22## or a 1- or 2-naphthylthio of the formula ##STR23## R.sub.9 is keto or ##STR24## R.sub.10 is halogen or --Y--R.sub.16. R.sub.11, R'.sub.11, R.sub.12 and R'.sub.12 are independently selected from hydrogen and lower alkyl or R'.sub.11, R.sub.12 and R'.sub.12 are hydrogen and R.sub.11 is ##STR25## R.sub.13 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl.
European Patent Application 0 012 401 published June 25, 1980 discloses carboxyalkyl dipeptide derivatives which are said to be angiotensin converting enzyme inhibitors and have the formula ##STR36## wherein R and R.sup.6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy (dimethylaminoethoxy), acylamino lower alkoxy (acetylaminoethoxy), acyloxy lower alkoxy (pivaloyloxymethoxy), aryloxy, such as phenoxy, arloweralkoxy, such as benzyloxy, substituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo or methoxy, amino, loweralkylamino, diloweralkylamino, hydroxyamino, arloweralkylamino such as benzylamino;
Example 41 of the subject European Patent Application describes the preparation of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.